There are two types of pains: acutely occurring pains as a self-warning to living organisms and chronically developing pains as an illness. While there is a demand for recovery from chronic pains by treatments, including drugs, a normegligible number of patients suffer intractable diseases for which no therapies have been established because the causal mechanism of onset remains unclear. Among them is generalized pain syndrome. Generalized pain syndrome is a disease of unknown cause that produces intense pain over a wide area of the body, and it is difficult to detect ecologically abnormal findings by examinations. Because generalized pain syndrome tends to often become chronic, it is positioned as an intractable chronic pain. Not only patients experience disturbances in their daily activities and labor, but also there are not a few cases wherein they have mental concerns, including the inability to determine which department to visit, the lack of an established diagnosis, even by extensive examinations, due to the low availability of specialist physicians, the absence of therapeutic drugs, being deemed idle, and the like. In fact, it is known that in addition to pains, generalized pain syndrome is often complicated by a sensation of fatigue, depression, anxiety and the like. Additionally, fibromyalgia, a form of generalized pain syndrome, occurs most prevalently among middle-aged to elderly women, and it has been found that physical traumas from surgery or accidents and stress-related mental factors are profoundly involved in the background of the onset.
Lysophosphatidic acid (LPA) is a lipid mediator produced at the time of tissue damage, known to act on 7-pass transmembrane receptors (LPA1, LPA2, LPA3) that couple with various G proteins (Gq/11/14, G12/13, Gi/o) to serve as a trophic factor for various cells, including nerve and glial cells.
The present inventor, through many years of research into the molecular mechanisms behind neuropathic pains, revealed that LPA is a substance that induces neuropathic pains, and reported that nerve injury-induced pain does not develop when a receptor of LPA is lacked using knockout mice prepared by knock out of LPA1, a kind of LPA receptor (Non-patent Documents 1 and 2).
The present inventor demonstrated that LPA is synthesized from lysophosphatidylcholine (LPC), which is a constituent of the cell membrane, by the LPA synthetase autotaxin (ATX), and is involved in irritation development (Non-patent Documents 3 and 4).